Structure of human succinic semialdehyde dehydrogenase gene: identification of promoter region and alternatively processed isoforms

Blasi, Paola; Boyl, Pietro Pilo; Ledda, Mario; Novelletto, Andrea; Gibson, K. Michael; Jakobs, Cornelis; Hogema, Boris M.; Akaboshi, Shinjiro; Loreni, Fabrizio; Malaspina, Patrizia

doi:10.1016/s1096-7192(02)00105-1

Cited by 51 publications

(73 citation statements)

References 31 publications

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“…This would also be compatible with the genotype of Patients 25 and 34. In our limited population survey [Blasi et al, 2002], we did not detect this type of chromosome, showing that it is rare at least in the European population. However, we detected chromosomes carrying both 538(T) and 545(T) with a frequency of about 10% [Blasi et al, 2002].…”

Section: Results Genotypingcontrasting

confidence: 64%

“…Nine of the mutations resulted in an almost complete loss of SSADH activity (o5%) and can be considered causative for SSADH deficiency. Four of the mutant alleles detected during the course of this study cause a decrease in SSADH activity of less than 55%, and their occurrence in the general European population has been reported elsewhere [Blasi et al, 2002]. These alleles can be considered to be nonpathogenic polymorphisms since carriers of SSADH deficiency do not have increased GHB levels in bodily fluids, nor do they display clinical symptoms even though SSADH activity is reduced to approximately 50%.…”

Section: Expression Studiessupporting

confidence: 52%

“…However, in several cases it was visible as noise below the stronger signal of the normal sequence. Because it is likely that the splice variant lacks activity [Blasi et al, 2002], it is possible that a higher relative expression level of exon 4B contributes to disease pathology.…”

Section: Results Genotypingmentioning

confidence: 99%

“…Missense mutations detected in patients were introduced into a pAD1/RSV-driven expression vector described previously [Blasi et al, 2002] using the 'quickchange' site-directed mutagenesis kit (Stratagene, La Jolla, CA) as recommended by the manufacturer.…”

Section: Functional Analysis Of Aldh5a1 Allelesmentioning

confidence: 99%

“…The open reading frame consists of 1,605 bp, encoding 535 amino acids, of which the first 47 residues form the mitochondrial targeting sequence [Chambliss et al, 1995[Chambliss et al, , 1998Trettel et al, 1997]. Recently we described the complete genomic structure of the gene and found an alternatively spliced small exon which may encode a novel isoform of the enzyme with an additional 13 amino acids [Blasi et al, 2002].…”

Section: Introductionmentioning

confidence: 99%

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Mutational spectrum of the succinate semialdehyde dehydrogenase (ALDH5A1) gene and functional analysis of 27 novel disease-causing mutations in patients with SSADH deficiency

et al. 2003

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Communicated by Johannes ZschockeSuccinate semialdehyde dehydrogenase (SSADH; ALDH5A1) deficiency, a rare metabolic disorder that disrupts the normal degradation of GABA, gives rise to a highly heterogeneous neurological phenotype ranging from mild to very severe. The nature of the mutation has so far been reported in patients from six families world wide and eight different mutations were described. Here we report the mutational spectrum in 48 additional unrelated families of different geographic origin. We detected 27 novel mutations at the cDNA level, of which 26 could be attributed to changes at the genomic level. Furthermore, six mutations were detected that did not strongly affect SSADH activity when expressed in HEK 293 cells and are considered nonpathogenic allelic variants. Twenty of the mutations were only found in one family. The spectrum of disease-causing mutations from all patients sequenced thus far consists of 25 point mutations, four small insertions, and five small deletions. Seven of these mutations affect splice junctions, seven are nonsense mutations, and 12 are missense mutations. Although there were no mutational hotspots or prevalent mutations responsible for a significant number of cases, 14 out of 37 (38%) of the missense alleles were present in exon 4 or 5. With one exception, the missense mutations we consider to be causative of SSADH deficiency reduced the SSADH activity to less than 5% of the normal activity in our in vitro expression system. This indicates that residual expression is not likely to be an important factor contributing to the large phenotypic differences observed among different families and even among siblings, suggesting that other modifying factors are of great importance in disease pathology. Hum Mutat 22:442-450,

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Section: Results Genotypingcontrasting

confidence: 64%

Section: Expression Studiessupporting

confidence: 52%

Section: Results Genotypingmentioning

confidence: 99%

Section: Functional Analysis Of Aldh5a1 Allelesmentioning

confidence: 99%